Evidence has established the protective effect of folic acid (FA) fortification and periconceptional supplementation on neural tube defects (NTDs). Folic acid fortification and periconceptional supplementation of women may reduce the risk of certain childhood cancers in their offspring. However, recent human studies have suggested that FA supplementation and fortification may promote the progression of already existing, undiagnosed, preneoplastic and neoplastic lesions, thereby corroborating earlier observations from animal and in vitro studies. Following the success of mandatory FA fortification on the reduction of NTD rates in the United States and Canada, several countries are currently considering whether or not, and at what dose, to institute FA fortification. Future debates and decisions regarding FA fortification should take into consideration all potential adverse effects and dose-responses of such a measure because it may be associated with very serious consequences for many generations. In addition to careful monitoring of adverse effects, preclinical and population-based studied are warranted in order to determine the efficacy, safety, and potential deleterious effects of FA fortification and supplementation on cancer risk and other health outcomes.